U.S. patent number 4,077,955 [Application Number 05/769,633] was granted by the patent office on 1978-03-07 for amino derivatives of 1,2,3,4-tetrahydro-2-oxopyrido[2,2-b]-pyrazine carboxylic acids and esters.
This patent grant is currently assigned to E. R. Squibb & Sons, Inc.. Invention is credited to Theodor Denzel, Hans Hoehn.
United States Patent |
4,077,955 |
Denzel , et al. |
March 7, 1978 |
Amino derivatives of 1,2,3,4-tetrahydro-2-oxopyrido[2,2-b]-pyrazine
carboxylic acids and esters
Abstract
Amino derivatives of
1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]-pyrazine carboxylic acid and
esters and their acid addition salts which have the general formula
##STR1## are useful as anti-inflammatory agents and central nervous
system depressants.
Inventors: |
Denzel; Theodor (Regensburg,
DT), Hoehn; Hans (Tegernheim, DT) |
Assignee: |
E. R. Squibb & Sons, Inc.
(Princeton, NJ)
|
Family
ID: |
25086053 |
Appl.
No.: |
05/769,633 |
Filed: |
February 17, 1977 |
Current U.S.
Class: |
544/350; 544/117;
544/131; 544/365; 544/58.6; 546/307; 546/318 |
Current CPC
Class: |
C07D
213/80 (20130101); C07D 471/04 (20130101) |
Current International
Class: |
C07D
213/00 (20060101); C07D 213/80 (20060101); C07D
471/04 (20060101); C07D 471/00 (20060101); A61K
031/53 (); C07D 471/04 () |
Field of
Search: |
;260/25BC |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Daus; Donald G.
Assistant Examiner: Turnipseed; James H.
Attorney, Agent or Firm: Levinson; Lawrence S. Smith; Merle
J.
Claims
What is claimed is:
1. A compound of the formula ##STR29## wherein R and R.sup.2 each
is hydrogen or lower alkyl; R.sup.1 is hydrogen, lower alkyl,
di(lower alkylamino)lower alkylene, and pharmacuetically acceptable
acid addition salts thereof.
2. A compound as in claim 1 wherein R is hydrogen or lower alkyl of
1 to 4 carbon atoms; R.sup.1 is hydrogen, lower alkyl of 1 to 4
carbon atoms, or di(lower alkylamino)lower alkylene; and R.sup.2 is
lower alkyl.
3. A compound as in claim 1 wherein R is ethyl; R.sup.2 is methyl;
and R.sup.1 has the same meaning as in claim 2.
4. A compound as in claim 1 wherein R, R.sup.1 and R.sup.2 each is
lower alkyl.
5. A compound as in claim 1 wherein R is ethyl, R.sup.2 is methyl
and R.sup.1 is butyl.
6. A compound as in claim 1 wherein R is ethyl, R.sup.2 is methyl,
and R.sup.1 is methylpropyl.
7. A compound as in claim 1 wherein R and R.sup.2 each is lower
alkyl and R.sup.1 is di(lower alkylamino)lower alkylene.
8. A compound as in claim 1 wherein R is ethyl, R.sup.2 is methyl
and R.sup.1 is dimethylaminopropyl.
9. A compound as in claim 1 wherein R is ethyl, R.sup.2 is methyl
and R.sup.1 is dimethylaminoethyl.
Description
SUMMARY OF THE INVENTION
In prior U.S. Pat. Nos. 3,935,222, Jan. 27, 1976, and 3,984,412,
Oct. 5, 1976, it was found that certain
tetrahydropyrazolo[3,4-b]pyridin-6-one derivatives and
pyrido[2,3-b]pyrazine carboxylic acid and ester derivatives,
respectively, have central nervous system and anti-inflammatory
properties. It has now been found that new amino derivatives of
1,2,3,4-tetrahydro-2-oxo-pyrido[2,3-b]pyrazine-7-carboxylic acids
and esters and acid addition salts thereof which have the general
formula ##STR2## have central nervous system depressant and
anti-inflammatory properties.
The symbols in the foregoing formula and throughout this
specification have the following meanings.
R and R.sup.2 each is hydrogen or lower alkyl.
R.sup.1 is hydrogen, lower alkyl, phenyl, substituted phenyl or the
lower alkyl may also bear an amino group ##STR3## wherein R.sup.3
and R.sup.4 each is lower alkyl or R.sup.3 and R.sup.4 together
with the nitrogen may form a heterocyclic radical like morpholino,
thiamorpholino, piperazino or piperidino. In other words, R.sup.1
represents the amino-lower alkylene group -lower ##STR4## wherein
R.sup.3 and R.sup.4 each is lower alkyl or combine to complete one
of the heterocyclics named above, i.e., R.sup.1 includes di(lower
alkyl)amino-lower alkylene, morpholino-lower alkylene,
thiamorpholino-lower alkylene, piperazino-lower alkylene or
piperidino-lower alkylene.
The lower alkyl groups in any of the foregoing radicals include
straight or branched chain hydrocarbon groups containing 1 to 7
carbon atoms. Examples of the groups contemplated are methyl,
ethyl, propyl, isopropyl etc. Lower alkyl groups of 1 to 4 carbon
atoms are preferred, especially the 1 and 2 carbon members of this
group. The lower alkylene groups are of similar type. The
substituted phenyl groups include one or two simple substituents
(preferably only one substituent, but they are the same groups if
disubstituted), i.e., lower alkyl, lower alkoxy, halogen (F, Cl, Br
or I, preferably Cl or BR), CF.sub.3, amino or carboxy. Examples of
the types of groups contemplated are o-, m- or p-chlorophenyl, o-,
m- or p-tolyl, 2,5-dichlorophenyl, 3,5-dimethylphenyl or
3,4-dimethoxyphenyl.
Preferred embodiments of this invention are as follows:
R is hydrogen or lower alkyl of 1 to 4 carbon atoms, especially
ethyl.
R.sup.1 is hydrogen, lower alkyl of 1 to 4 carbon atoms, especially
butyl or methylpropyl, di(lower alkyl)amino (lower alkylene),
especially dimethylaminoethyl or dimethylaminopropyl, or
morpholino-lower alkylene, especially morpholinopropyl.
R.sup.2 is lower alkyl, especially methyl.
DETAILED DESCRIPTION
The new compounds of formula I are formed by the following series
of reactions.
A 4,6-dihydroxypyridine carboxylic acid ester of the formula
##STR5## [produced analogous to the procedure described in Chem.
Ber. 99, 244 (1966)] wherein R is lower alkyl, is made to react
with an inorganic acid chloride like phosphorus oxychloride,
producing a dichloro compound of the formula ##STR6## This compound
is now treated with an amine H.sub.2 NR.sup.1 in the presence of a
base, e.g., an alkylamine like triethylamine, forming a compound of
the formula ##STR7##
Reaction of the compound of formula IV with a glycine ester (or its
salt) of the formula
in an alcohol solvent like methanol in the presence of a base like
triethylamine, preferably heating at about reflux temperature,
produces a compound of the formula ##STR8##
Hydrogenation of this product, e.g., catalytically in the presence
of palladium-carbon, results in the formation of the compound of
formula I.
The ester can be converted to the acid, i.e., wherein R is
hydrogen, with a dilute alkali hydroxide like sodium hydroxide.
The bases of formula I form acid addition salts by reaction with an
equivalent amount of one of the common inorganic and organic acids.
Such salts include the hydrohalides, e.g., hydrobromide,
hydrochloride, sulfate, nitrate, phosphate, acetate, citrate,
oxalate, tartrate, maleate, succinate, benzoate, ascorbate,
alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g.,
benzenesulfonate, etc. It is frequently convenient to purify or
isolate the product by forming an insoluble salt which is not
necessarily physiologically acceptable. The base is then obtained
by neutralization and another salt can then be formed by treatment
with the appropriate inorganic and organic acid.
The new compounds of this invention have anti-inflammatory
properties and are useful, for example, to reduce local
inflammatory conditions such as those of an edematous nature or
resulting from proliferation of connective tissue in various
mammalian species such as rats, dogs and the like when given orally
in dosages of about 10 to 50 mg/kg/day, preferably 10 to 25
mg/kg/day, in single or 2 to 4 divided doses, as indicated by the
carageenan edema assay in rats. The active substance can be
utilized in compositions such as tablets, capsules, solutions or
suspensions containing up to about 300 mg. per unit of dosage of a
compound or mixture of compounds of formula I or physiologically
acceptable acid addition salt thereof. They are compounded in
conventional manner with a physiologically acceptable vehicle or
carrier, excipient, binder, preservative, stabilizer, flavor, etc.
as called for by accepted pharmaceutical practice. Topical
preparations containing about 0.01 to 3 percent by weight of active
substance in a lotion, salve or cream can also be used.
The compounds of this invention are also central nervous system
depressants and can be used as tranquilizers or ataractic agents
for the relief of anxiety and tension states, for example, in mice,
cats, rats, dogs and other mammalian species. For this purpose, a
compound or mixture of compounds of formula I, or non-toxic,
physiologically acceptable acid addition salt thereof, is
administered orally or parenterally in a conventional dosage form
such as tablet, capsule, injectable or the like. A single dose, or
preferably 2 to 4 divided daily doses, provided on a basis of about
3 to 50 mg. per kg. per day, preferably about 3 to b 15 mg. per kg.
per day, is appropriate. A conventional dosage in oral or
parenteral form is compounded by incorporating about 10 to 250 mg.
per unit of dosage with conventional vehicle, excipient, binder,
preservative, stabilizer, flavor or the like as called for by
accepted pharmaceutical practice.
The following examples constitute preferred embodiments and also
illustrate how these and other members of the group are produced.
Simple variation of the reactants and substitution in the reaction
sequences described below readily yield other compounds within the
scope of the invention. All temperatures are in degrees
celsius.
EXAMPLE 1
1,2,3,4-Tetrahydro-6-methyl-8-[(1-methylpropyl)amino]-2-oxopyrido[2,3-b]pyr
azine-7-carboxylic acid, ethyl ester
a. 4,6-Dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl
ester
242 g. of 4,6-dihydroxy-2-methyl-5-nitropyridine-3-carboxylic acid,
ethyl ester (1 Mol.) are heated at 80.degree. with 500 ml. of
phosphorus oxychloride for 60 hours. After this time, the excess
phosphorus oxychloride is decomposed by pouring into ice water. The
precipitate is filtered off and recrystallized from petroleum ether
using charcoal, yield: 195 g. (70%); m.p.
45.degree.-46.degree..
b.
6-Chloro-2-methyl-4-(1-methylpropyl)amino-5-nitropyridine-3-carboxylic
acid, ethyl ester
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic
acid, ethyl ester (0.5 Mol.) are dissolved in about 500 ml.
methanol. 60 g. of triethylamine are added and the solution is
heated at reflux temperature. At this point, 36.5 g. of sec.
butylamine are added dropwise. After the addition is completed,
heating is continued for 10 minutes. The solvent is then removed in
vacuo and 500 ml. of ethyl acetate are added to the residue. The
triethylamine hydrochloride is filtered off and the solvent
evaporated. The resulting yellow oil,
6-chloro-2-methyl-4-(1-methylpropyl)amino-5-nitropyridine-3-carboxylic
acid, ethyl ester is recrystallized with methanol, yield: 107 g.
(68%); m.p. 33.degree.-35.degree. (methanol).
c.
6-(Ethoxycarbonylmethyl)amino-2-methyl-4-(1-methylpropyl)amino-5-nitropyri
dine-3-carboxylic acid, ethyl ester
18.7 g. of
6-chloro-2-methyl-4-(1-methylpropyl)amino-5-nitropyridine-3-carboxylic
acid, ethyl ester, 8.2 g. of glycine ester hydrochloride and 19 g.
of triethylamine are refluxed in 200 ml. of alcohol for 4 hours.
The solution is evaporated to dryness, and the residue extracted
with 200 ml. of diethyl ether. The ether is removed by distillation
and the residue,
6-(ethoxycarbonylmethyl)amino-2-methyl-4-(1-methylpropyl)amino-5-nitropyri
dine-3-carboxylic acid, ethyl ester is recrystallized from
methanol, yield: 16.2 g. m.p. 43.degree.-45.degree..
d.
1,2,3,4-Tetrahydro-6-methyl-8-[(1-methylpropyl)amino]-2-oxo-pyrido[2,3-b]p
yrazine-7-carboxylic acid, ethyl ester
16 g. of the product of Example 1c are dissolved in 200 ml. of
butanol. About 0.1 g. of palladium on charcoal (10%) is added and
the mixture is hydrogenated at 100.degree. at ordinary pressure.
After the theoretical amount of hydrogen has been absorbed, the
catalyst is filtered off and the solvent removed in vacuo. The
residue,
1,2,3,4-tetrahydro-6-methyl-8-[(1-methylpropyl)amino]-2-oxo-pyrido[2,3-b]p
yrazine-7-carboxylic acid, ethyl ester is recrystallized from
methanol, yield: 7.2 g.; m.p. 157.degree.-159.degree.. Treatment
with dilute sodium hydroxide solution yields
1,2,3,4-tetrahydro-6-methyl-8[(1-methylpropyl)amino]-2-oxopyrido[2,3-b]pyr
azine-7-carboxylic acid.
EXAMPLE 2
8-(Butylamino)-6-methyl-1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]-pyrazine-7-ca
rboxylic acid, ethyl ester
When the sec. butylamine is replaced by n-butylamine, in part b of
the procedure of Example 1,
4-butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid,
ethyl ester is obtained; m.p. 33.degree.-35.degree. (methanol).
This compound is processed as described in Example 1c and 1d
through the reaction with glycine ester, followed by the
hydrogenation step. By this procedure,
8-(butylamino)-6-methyl-1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]pyridine-7-ca
rboxylic acid, ethyl ester is obtained, yield: 73%; m.p.
186.degree.-188.degree. (methanol).
EXAMPLE 3
8[[2-(Dimethylamino)propyl]amino]-1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]pyra
zine-7-carboxylic acid, ethyl ester
a.
4-[[3-(Dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-car
boxylic acid, ethyl ester
139 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid,
ethyl ester (0.5 Mol.) of Example 1a are dissolved in about 500 ml.
of methanol. 60 g. of triethylamine are added and the solution is
heated at reflux temperature. At this point, 50 .1 g. of
[3-(dimethylamino)propyl]amine are added dropwise. After the
addition is completed, heating is continued for 10 minutes. The
solvent is removed in vacuo and the residue is suspended in 200 ml.
of water. The aqueous mixture is made alkaline with 10% sodium
hydroxide solution and extracted three times with 200 ml. portions
of ethyl acetate. The organic layer is dried over calcium chloride,
evaporated to dryness and crystallized with petroleum ether to
obtain
4-[[3-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-car
boxylic acid, ethyl ester, yield: 102 g. (59%); m.p.
20.degree..
b.
8-[[3-(Dimethylamino)propyl]amino]-1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]py
razine-7-carboxylic acid, ethyl ester
17.6 g. of 4-[[3
-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-carboxyl
ic acid, ethyl ester, 7.4 g. of glycine ethyl ester, hydrochloride
and 11 g. of triethylamine are refluxed together with stirring in
200 ml. of alcohol for 4 hours. After this time, the solvent is
removed in vacuo and the residue treated with aqueous sodium
hydroxide solution. The mixture is extracted three time with 50 ml.
portions of ethyl acetate. The extracts are combined, about 0.5 g.
palladium on charcoal is added and the mixture is hydrogenated at 3
atmospheres hydrogen pressure and 60.degree.. When the theoretical
amount of hydrogen is absorbed, the reaction is stopped, the
catalyst filtered off and the solvent removed in vacuo. The
crystalline residue,
8-[[3-(dimethylamino)propyl]amino]-1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]py
razine-7-carboxylic acid, ethyl ester is purified by
recrystallization from methanol, yield: 8 g., m.p.
163.degree.-165.degree..
The hydrochloride salt is formed by treating the above product with
ethanolic hydrogen chloride.
EXAMPLE 4
8-[[2-(Dimethylamino)ethyl]amino]-1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]pyra
zine-7-carboxylic acid, ethyl ester
By substituting [2-(dimethylamino)ethyl]amine for the
[3-(dimethylamino)propyl]amine in the procedure of Example 3a and
this compound is processed as described in Example 3a and 3b,
8-[[2-(dimethylamino)ethyl]amino]-1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]pyr
azine-7-carboxylic acid, ethyl ester is obtained, m.p.
183.degree.-185.degree. (methanol).
EXAMPLE 5
1,2,3,4-Tetrahydro-6-methyl-8-[[3-(4-morpholinyl)propyl]amino]-2-oxopyrido[
2,3-b]pyrazine-7-carboxylic acid, ethyl ester
When the [3-(dimethylamino)propyl]amine is replaced by
[3-(4-morpholinyl)propyl]amine in the procedure of Example 3a and
this compound processed as described in Example 3a and 3b,
1,2,3,4-tetrahydro-6-methyl-8-[[3-(4-morpholinyl)propyl]amino]-2-oxopyrido
[2,3-b]pyrazine-7-carboxylic acid, ethyl ester is obtained, m.p.
168.degree.-170.degree. (methanol).
The following additional products are obtained by the procedure of
Example 1 by appropriate substitution for the
4,6-dihydroxy-2-methyl-5-nitropyridine-3-carboxylic acid ester in
part a and/or substitution for the butylamine in part b:
______________________________________ ##STR9## Example R R.sup.1
R.sup.2 ______________________________________ 6 H C.sub.4 H.sub.9
H 7 C.sub.2 H.sub.5 H CH.sub.3 8 C.sub.2 H.sub.5 C.sub.2 H.sub.5
CH.sub.3 9 C.sub.2 H.sub.5 C.sub.3 H.sub.7 H 10 C.sub.2 H.sub.5
CH.sub.3 C.sub.2 H.sub.5 11 H ##STR10## H 12 C.sub.2 H.sub.5
##STR11## CH.sub.3 13 H ##STR12## H 14 CH.sub.3 ##STR13## H 15
C.sub.2 H.sub.5 ##STR14## H 16 C.sub.2 H.sub.5 ##STR15## CH.sub.3
17 C.sub.2 H.sub.5 ##STR16## CH.sub.3 18 C.sub.2 H.sub.5 ##STR17##
H 19 C.sub.2 H.sub.5 ##STR18## H 20 CH.sub.3 ##STR19## H 21 H
##STR20## H 22 C.sub.3 H.sub.7 CH.sub.2 CH.sub.2 N(C.sub.2
H.sub.5).sub.2 C.sub.2 H.sub.5 23 H CH.sub.2 CH.sub.2
N(CH.sub.3).sub.2 H 24 H CH.sub.3 H 25 H ##STR21## CH.sub.3 26
C.sub.2 H.sub.5 ##STR22## H 27 H (CH.sub.2).sub.3 N(C.sub.2
H.sub.5).sub.2 H 28 C.sub.2 H.sub.5 C.sub.4 H.sub.9 C.sub.4 H.sub.9
29 C.sub.2 H.sub.5 C.sub.4 H.sub.9 H 30 C.sub.4 H.sub.9 CH.sub.3
CH.sub.3 31 H H H 32 C.sub.2 H.sub.5 H CH.sub.3 33 C.sub.2 H.sub.5
##STR23## H 34 H ##STR24## CH.sub.3 35 C.sub.2 H.sub.5 ##STR25##
CH.sub.3 36 H ##STR26## CH.sub.3 37 C.sub.2 H.sub.5 ##STR27## H 38
H ##STR28## H
* * * * *